Origin of life researchers figure out how to build bigger RNAs

Pre-biochemistry can link small building blocks into bigger molecules.

We'll probably never know exactly how life on Earth got its start. The conditions in which it began have long since been lost, and there are simply too many precursor molecules and potential environments that could have gotten the process going. Nevertheless, researchers hope to put together a pathway that's at least plausible, starting from simple molecules that were present on the early Earth and building up to an enclosed system with basic inheritance (from there, evolution can take over).

A lot of progress has been made in understanding how a simple chemical, like hydrogen cyanide, can be built up through a series of reactions into a nucleotide, the basic building block of molecules like DNA and RNA. And we've learned quite a bit about how larger RNAs (more than 100 nucleotides long) can fold into complex structures that can catalyze reactions and undergo the chemical equivalent of Darwinian evolution. The challenge has been bridging the gap between the two, going from a handful of linked nucleotides to a large molecule that's potentially capable of catalyzing chemical reactions.

Now, the team that developed the earlier results is back with another publication. Their latest work shows how short molecules that are composed of just a handful of nucleotides can be linked together, eventually building longer, more complex chains. Once again, the chemistry is simple enough to occur on the early Earth, and the reaction might explain a curious bias in how DNA and RNA are built into long chains of nucleotides.

To understand the chemistry, it's critical to understand the structure of DNA and RNA. Both have a linked backbone that alternates between phosphates (in red) and sugars that are formed into a five-atom ring (in blue, with the O on top). In RNA, the two lower corners of the ring (positions 2 and 3, counting clockwise from the O) are chemically very similar in that they both have oxygens hanging off them. In the chemical synthesis described in one of the previous papers, the authors found that the phosphate was linked to both position 2 and 3, instead of only being linked to position 3.

The authors were curious about how the exclusive bias toward position 3 occurred, so they considered the possibility that another chemical reaction could knock the phosphate off position 2. They tested a very simple compound, one containing only two carbons: thioacetate, which can form spontaneously through the reaction of carbon monoxide and hydrogen sulfate. Both of these carbons are expected to be present in the atmosphere of the early Earth.

The reaction worked, and it had a strong preference for attaching an acetate to the carbon at position 2. That result left the phosphate hanging off position 3, like it normally is in the DNA and RNA used by existing life.

But that result wasn't the only thing this reaction changed. By altering the chemical environment near the phosphate, the resulting nucleotide became more reactive. Normally, these nucleotides will only react spontaneously to form chains a handful of nucleotides long. But with the acetate added, two of these short pieces would spontaneously link together, forming part of a longer RNA chain.

(This reaction required a third, short piece of RNA before it would occur. This third piece base-paired with both of the first two, lining them up so that the bits that underwent the reaction were in close proximity. Although this piece was supplied by the authors in this paper, in pre-biotic conditions, lots of random, short pieces of RNA would be around, so it isn't a problem from the perspective of whether this chemistry might work outside of the lab.)

There's nothing preventing this sort of reaction from occurring repeatedly, taking a large collection of short chains of nucleotides and gradually building up a significant piece of RNA from them. Since the starting material would have the individual nucleotides linked in a random order and lots of these reactions could occur in parallel, this situation could build up a large population of essentially random RNA molecules, and it's possible that some of those molecules could have catalytic activity.

Again, these findings don't mean that life definitively got its start through these acetylation reactions. But they do point the way toward a plausible path to large RNA molecules.

31 Reader Comments

I'm still uncomfortable with the notion of a RNA-without-protein-enzyme origin of life. At some point, we still have to get to the massive shift from "self-replicating RNA, proteins not involved" to "RNA that codes for proteins that are involved in the translation of that same RNA into those same proteins". This to me seems like the really big question, not whether simple polymerization reactions can or could have occurred in a particular set of conditions… and it's why I have this sneaking suspicion that this particular line of investigation (RNA-without-protein) may end up being a dead end.

I'm probably just showing how rusty my biochemistry is here: but would this selection for position 3 explain the right-handed twist of the eventual double-helix? Or is this related to the chirality of the sugars?

I'm still uncomfortable with the notion of a RNA-without-protein-enzyme origin of life. At some point, we still have to get to the massive shift from "self-replicating RNA, proteins not involved" to "RNA that codes for proteins that are involved in the translation of that same RNA into those same proteins". This to me seems like the really big question, not whether simple polymerization reactions can or could have occurred in a particular set of conditions… and it's why I have this sneaking suspicion that this particular line of investigation (RNA-without-protein) may end up being a dead end.

RNAs can have structures that allow them to act as reaction catalysts in a similar way to enzymes (look up "ribozymes"). From that point on, it's just a matter of time (and lots of iteration) for a system to evolve particular functions such as assembling other large and functional molecules such as peptides or DNA.

So it may be that the transition you describe is not such a huge leap after all.

I'm probably just showing how rusty my biochemistry is here: but would this selection for position 3 explain the right-handed twist of the eventual double-helix? Or is this related to the chirality of the sugars?

Neither, actually, as best as I understand it. The right-handedness of B-DNA is a result of it being the most stable conformation under normal conditions - hydrogen bonding between nucleotides along the chain, etc. But you can take the exact same strand of DNA and convert it into the other forms (A-DNA, Z-DNA, etc) under the right conditions - no need to change the positions of the phosphates or even the chirality of the sugar.

RNAs can have structures that allow them to act as reaction catalysts in a similar way to enzymes (look up "ribozymes"). From that point on, it's just a matter of time (and lots of iteration) for a system to evolve particular functions such as assembling other large and functional molecules such as peptides or DNA.

So it may be that the transition you describe is not such a huge leap after all.

Yes, I'm aware of ribozymes - that's the only way in which an "RNA-only" hypothesis would make any sense at all. But in this case, "just a matter of time (and lots of iteration)" underestimates the need for selective advantage to be increasing throughout all those iterations.

It's the circular nature of the "RNA codes for ribosomes, which in turn decodes the RNA" that I find to be a big leap here - it's a "chicken and egg" problem, and I find it hard to imagine a situation where an organism that already has a working RNA-as-ribozyme system would gain a selective advantage out of a brand-new, sub-optimal "RNA -> protein ribosome" system.

I'm still uncomfortable with the notion of a RNA-without-protein-enzyme origin of life. At some point, we still have to get to the massive shift from "self-replicating RNA, proteins not involved" to "RNA that codes for proteins that are involved in the translation of that same RNA into those same proteins". This to me seems like the really big question, not whether simple polymerization reactions can or could have occurred in a particular set of conditions… and it's why I have this sneaking suspicion that this particular line of investigation (RNA-without-protein) may end up being a dead end.

Have a look at any RNA-virus.

It will have RNA that encodes proteins. RNA will also catalyze formation of those proteins (rRNA is the catalytic part of ribosomes, protein bits are there just for the structure). Amino acids used for the synthesis of those proteins arrive there and chosen thanks to being coupled to tRNA.

I find it hard to imagine a situation where an organism that already has a working RNA-as-ribozyme system would gain a selective advantage out of a brand-new, sub-optimal "RNA -> protein ribosome" system. protein ribosome" system.

There's nothing sub-optimal about RNA->protein ribosome system. I don't have to time write concience list of things that offer selective advantage.

Just from the top of my head:

Proteins allow vastly more options for both biochemical catalysis, structures, regulation, more possibilities for different inorganic cofactors and coenzymes, possibility for building complex and advanced catalytic units composed of subunits (again more possibilities for regulation, post-catalytic modifications, etc.), hydrophobic parts of proteins allow them to span lipid bilayers (think of ribosome attached to the reticulum and being able to synthethise the gene product meant for extracellular space directly into vesicle that will get transported outside cell). And lots of other stuff.

RNA's limited nucleotide diversity and structural constraints rising form the 3D structure of nucleic acids just don't allow nearly as much much head room as a catalytic unit. Great for a community composed of simple replicators at the early stage though. Also great for encoding information.

EDIT:

Also you might interested about the PNA World -hypothesis (PNA = peptide nuleic acid, so basicily RNA+amino acids instead of pure RNA-world).

RNAs can have structures that allow them to act as reaction catalysts in a similar way to enzymes (look up "ribozymes"). From that point on, it's just a matter of time (and lots of iteration) for a system to evolve particular functions such as assembling other large and functional molecules such as peptides or DNA.

So it may be that the transition you describe is not such a huge leap after all.

Yes, I'm aware of ribozymes - that's the only way in which an "RNA-only" hypothesis would make any sense at all. But in this case, "just a matter of time (and lots of iteration)" underestimates the need for selective advantage to be increasing throughout all those iterations.

It's the circular nature of the "RNA codes for ribosomes, which in turn decodes the RNA" that I find to be a big leap here - it's a "chicken and egg" problem, and I find it hard to imagine a situation where an organism that already has a working RNA-as-ribozyme system would gain a selective advantage out of a brand-new, sub-optimal "RNA -> protein ribosome" system.

I see what you're saying but what if the step from ribozyme to primitive ribosome was pre-organism. At that point, anything that increases the reaction rate of a replicating system will be a 'selective advantage' for that system. In the same way that if I have a chemical reaction going in a flask, then most often I'll expect to see a major product together with one or more minor products. In a sense the major product has 'outcompeted' the minor ones but only because it was created through a faster reaction.

I can envisage the following sequence.

1. Small polynucleotides assemble into larger ones as per this article.2. Larger polynucleotides start replicating themselves, initially through a simple templating effect (single nucleotides attach to long polynucleotide by base-pairing and are now close enough to covalently link.)3. Polynucleotides become large enough to have significant secondary structure. 'Evolution' of improved replicators based on ribozymes.

4. Somewhere along the line, amino acids start attaching to single nucletides or small polynucleotides. The replicators are now primarily RNA based but with random encrustations of amino acids. If two amino acids end up sufficiently close together on the RNA, then they link up into small peptides attached to the RNA.

5. ???

6. Primitive ribosome that can replicate both its RNA and peptide parts.

7. Basic machinery now in place for creating random peptides

8. 'Evolution' of random peptides.

The tricky bit of course is 5, which is the transition from 'nucleotide fragments with random amino acids attached' to 'nucleotide fragments with specific amino acids attached' - effectively the origin of the present day genetic code.

in pre-biotic conditions, lots of random, short pieces of RNA would be around

How so? If we already have RNA around, doesn't it mean that we basically already have life around and we need to get back further.

No, the entire point of the RNA World hypothesis is the idea that RNA molecules pre-dated actual life.

Quote:

How did RNA occur spontaneously if it didn't come from life?

Complex organic chemistry under just the right conditions with lots of time, is the short answer that tells you almost nothing. RNA would have assembled itself out of free-floating nucleotides, which themselves would have come from simpler organic molecules. In the same way we can take really simple ingredients like methane and ammonia in water to make amino acids, nucleotides may have formed gradually under naturally occurring conditions.

in pre-biotic conditions, lots of random, short pieces of RNA would be around

How so? If we already have RNA around, doesn't it mean that we basically already have life around and we need to get back further. How did RNA occur spontaneously if it didn't come from life?

As i tried to explain it:Basic chemistry (as identified by these authors) can create the individual nucleotides. They can combine into short oligomers, but don't spontaneously assemble into large RNA molecules, the sorts that are catalytic. So, under these chemical conditions, you have lots of short pieces. This work shows how these can be assembled into large, potentially catalytic ones.

Maybe it's an easier explanation to follow if it's in a condensed form?

RNAs can have structures that allow them to act as reaction catalysts in a similar way to enzymes (look up "ribozymes"). From that point on, it's just a matter of time (and lots of iteration) for a system to evolve particular functions such as assembling other large and functional molecules such as peptides or DNA.

So it may be that the transition you describe is not such a huge leap after all.

Yes, I'm aware of ribozymes - that's the only way in which an "RNA-only" hypothesis would make any sense at all. But in this case, "just a matter of time (and lots of iteration)" underestimates the need for selective advantage to be increasing throughout all those iterations.

It's the circular nature of the "RNA codes for ribosomes, which in turn decodes the RNA" that I find to be a big leap here - it's a "chicken and egg" problem, and I find it hard to imagine a situation where an organism that already has a working RNA-as-ribozyme system would gain a selective advantage out of a brand-new, sub-optimal "RNA -> protein ribosome" system.

"...I find it hard to imagine..." and there you have the bane of attempts to think intuitively about evolution. Natural selection has no bias whatsoever towards solutions we find it easy to imagine. That is also the root cause behind the failure of imagination that is "intelligent design."

Interesting, that's for sure. We keep edging closer to a fully plausible set of steps which could give rise to something close enough to alive not to matter. In another 30 or 40 years we'll probably have worked out a fairly detailed set of steps. As John says though, we'll never know what actually happened on the early Earth. There are also questions beyond the low level detailed chemistry, such as what exactly the initial environment looked like. Did these reactions take place in crevices in seafloor vents, inside membranes made of nonbiological emolients, in ice, clay, tidal pools? How were additional attributes of current life acquired? All fascinating and probably unanswerable questions. Damn I would like a TARDIS.

RNAs can have structures that allow them to act as reaction catalysts in a similar way to enzymes (look up "ribozymes"). From that point on, it's just a matter of time (and lots of iteration) for a system to evolve particular functions such as assembling other large and functional molecules such as peptides or DNA.

So it may be that the transition you describe is not such a huge leap after all.

Yes, I'm aware of ribozymes - that's the only way in which an "RNA-only" hypothesis would make any sense at all. But in this case, "just a matter of time (and lots of iteration)" underestimates the need for selective advantage to be increasing throughout all those iterations.

It's the circular nature of the "RNA codes for ribosomes, which in turn decodes the RNA" that I find to be a big leap here - it's a "chicken and egg" problem, and I find it hard to imagine a situation where an organism that already has a working RNA-as-ribozyme system would gain a selective advantage out of a brand-new, sub-optimal "RNA -> protein ribosome" system.

Ah, but that's the part where the older knowledge proved incorrect. That knowledge viewed the ribosomal RNA only as a 'scaffold' for the ribosomal proteins. However, it turns out it's the other way around the ribosomal RNA is actually the catalytic part of a ribosome and the ribosomal proteins are the structural part.The ribosome is in fact itself a ribozyme!

I take solace in the fact that astronomy has been a rigorous science much longer than biology and predated the Pope and the Vatican. We can blame them for the lack of biology, RNA/DNA knowledge as well as the suppression of Galileo.

Small nit-pick about the wording in the article. You say that the red phosphates like to connect to positions 2 and 3 when counting clockwise from the oxygen atom at the top of the blue ring. However in the picture they are connected to the 2nd and 3rd position counter-clockwise from said oxygen. Am I misunderstanding something or is the wording/picture backwards?

"...I find it hard to imagine..." and there you have the bane of attempts to think intuitively about evolution.

Richard Dawkins calls this the "Argument from insufficient imagination". As in, "There is no way something this complex could have evolved naturally," which really means "I can't think of any way something this complex could have evolved naturally."

Humans are not evolved to have an intuitive understanding of the time scales involved here. Four billion years is a long time.

Small nit-pick about the wording in the article. You say that the red phosphates like to connect to positions 2 and 3 when counting clockwise from the oxygen atom at the top of the blue ring. However in the picture they are connected to the 2nd and 3rd position counter-clockwise from said oxygen. Am I misunderstanding something or is the wording/picture backwards?

So, start at the O. Go right/down to carbon one, left and down to position two, left to position 3. Position four is up/left, and then straight up to carbon 5, which connects to the phosphate.

"...I find it hard to imagine..." and there you have the bane of attempts to think intuitively about evolution. Natural selection has no bias whatsoever towards solutions we find it easy to imagine. That is also the root cause behind the failure of imagination that is "intelligent design."

Is there any reason why these chemical processes (whatever they would have been) would have stopped happening outside lab settings? Or, perhaps better phrased, did they stop?

Ie. is new life still being created right now all around us? And by new life, I don't mean newborns from existing species, but new species altogether.

Though theoretically possible, I'd say the answer is no. Key here is time. The chance of these chemical processes happening are as good as none, but since we are here they obviously can happen. So given lots and lots of time, billions of years I guess, life may arise.

It will evolve incredibly slowly though, so if the first molecules of a potential new kind of life are present in our oceans, chances are we won't recognise them for what they might become.

Is there any reason why these chemical processes (whatever they would have been) would have stopped happening outside lab settings? Or, perhaps better phrased, did they stop?

Ie. is new life still being created right now all around us? And by new life, I don't mean newborns from existing species, but new species altogether.

The reactions that make adenine out of air and water and lightning are almost certainly still happening. The problem is that the newly-formed adenine immediately encounters a bacterium, which devours it as a tasty source of adenine. I don't think there's likely to be an area with the right raw materials and no currently-existing life in which things can evolve without becoming food.

Small nit-pick about the wording in the article. You say that the red phosphates like to connect to positions 2 and 3 when counting clockwise from the oxygen atom at the top of the blue ring. However in the picture they are connected to the 2nd and 3rd position counter-clockwise from said oxygen. Am I misunderstanding something or is the wording/picture backwards?

The image is missing the OH groups at position 2 on the rings. I assume they were left off for clarity, but if so shouldn't that have been specified in the figure caption?

Edit: and to clarify for the quoted poster, the phosphate could couple at the 2 or 3 (technically, 2' or 3') position, which then links to the terminal oxygen of the next unit (the 5 or 5' position). 5' and 3' are the linkage positions in RNA, though,

I see what you're saying but what if the step from ribozyme to primitive ribosome was pre-organism. At that point, anything that increases the reaction rate of a replicating system will be a 'selective advantage' for that system. In the same way that if I have a chemical reaction going in a flask, then most often I'll expect to see a major product together with one or more minor products. In a sense the major product has 'outcompeted' the minor ones but only because it was created through a faster reaction.

I can envisage the following sequence.

1. Small polynucleotides assemble into larger ones as per this article.2. Larger polynucleotides start replicating themselves, initially through a simple templating effect (single nucleotides attach to long polynucleotide by base-pairing and are now close enough to covalently link.)3. Polynucleotides become large enough to have significant secondary structure. 'Evolution' of improved replicators based on ribozymes.

4. Somewhere along the line, amino acids start attaching to single nucletides or small polynucleotides. The replicators are now primarily RNA based but with random encrustations of amino acids. If two amino acids end up sufficiently close together on the RNA, then they link up into small peptides attached to the RNA.

5. ???

6. Primitive ribosome that can replicate both its RNA and peptide parts.

7. Basic machinery now in place for creating random peptides

8. 'Evolution' of random peptides.

The tricky bit of course is 5, which is the transition from 'nucleotide fragments with random amino acids attached' to 'nucleotide fragments with specific amino acids attached' - effectively the origin of the present day genetic code.

No idea if this is even vaguely plausible though.

My modification to this:4. Supply of raw RNA begins to run low. Efficient capture of raw materials becomes the dominant selection factor.4.1 "efficient capture of raw materials" can include "disassemble other RNA molecules for parts." The predator-prey relationship begins.5 With the dominant selection factors now being "disassemble competing sequences faster" and "protect yourself from being disassembled", the strategy "Surround yourself with a shield of non-RNA junk" appears. Naturally this shield is pointless if it doesn't continue to allow the RNA to replicate and disassemble other sequences.5.1 Some peptide "junk" may serve a secondary function, like aiding proton transfer for hydrolysis or synthesis reactions, or binding the RNA in a conformation favorable for promoting such reactions. Repeat 4 and 4.1, replacing "RNA" with "RNA plus peptides"

Is there any reason why these chemical processes (whatever they would have been) would have stopped happening outside lab settings? Or, perhaps better phrased, did they stop?

Ie. is new life still being created right now all around us? And by new life, I don't mean newborns from existing species, but new species altogether.

The work described in the article supports the RNA-first generation of life, and RNA is incredibly sensitive to degradation. The awesome part of this is that pre-life earth would have no RNase activity, and therefore RNA stood a better chance of hanging around for a while. Nowadays, RNase is everywhere. You would never find the building blocks for RNA in the absence of RNase, so repeating the past is not happening.